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Background— Phosphoinositide 3-kinase (PI3K) p110 plays a key role in insulin action and tumorigenesis. Myocyte contraction is initiated by an inward Ca2+ current (ICa,L) through the voltage-dependent L-type Ca2+ channel (LTCC). The aim of this study was to evaluate whether p110 also controls cardiac contractility by regulating the LTCC.

Methods and Results— Genetic ablation of p110 (also known as Pik3ca), but not p110β (also known as Pik3cb), in cardiac myocytes of adult mice reduced ICa,L and blocked insulin signaling in the heart. p110-null myocytes had a reduced number of LTCCs on the cell surface and a contractile defect that decreased cardiac function in vivo. Similarly, pharmacological inhibition of p110 decreased ICa,L and contractility in canine myocytes. Inhibition of p110β did not reduce ICa,L.

Conclusions— PI3K p110 but not p110β regulates the LTCC in cardiac myocytes. Decreased signaling to p110 reduces the number of LTCCs on the cell surface and thus attenuates ICa,L and contractility.

Autophagy is an evolutionarily conserved cell renewal process that depends on phosphatidylinositol 3-phosphate (PtdIns(3)P). In metazoans, autophagy is inhibited by PtdIns(3,4,5)P3, the product of class IA PI3Ks, which mediates the activation of the Akt–TOR kinase cascade. However, the precise function of class IA PI3Ks in autophagy remains undetermined. Class IA PI3Ks are heterodimeric proteins consisting of an 85-kD regulatory subunit and a 110-kD catalytic subunit. Here we show that the class IA p110-β catalytic subunit is a positive regulator of autophagy. Genetic deletion of p110-β results in impaired autophagy in mouse embryonic fibroblasts, liver, and heart. p110-β does not promote autophagy by affecting the Akt–TOR pathway. Rather, it associates with the autophagy-promoting Vps34–Vps15–Beclin 1–Atg14L complex and facilitates the generation of cellular PtdIns(3)P. Our results unveil a previously unknown function for p110-β as a positive regulator of autophagy in multicellular organisms.